Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats

Mechanisms by which endothelin (ET)-1 mediates chronic pulmonary hypertension remain incompletely understood. Although activation of the ET type A (ETA) receptor causes vasoconstriction, stimulation of ET type B (ET_B) receptors can elicit vasodilation or vasoconstriction. We hypothesized that the ET_B receptor attenuates the development of hypoxic pulmonary hypertension and studied a genetic rat model of ET_B receptor deficiency (transgenic sl/sl). After 3 wk of severe hypoxia, the transgenic sl/sl pulmonary vasculature lacked expression of mRNA for the ET_B receptor and developed exaggerated pulmonary hypertension that was characterized by elevated pulmonary arterial pressure, diminished cardiac output, and increased total pulmonary resistance. Plasma ET-1 was five-fold higher in transgenic sl/sl rats than in transgenic controls. Although mRNA for prepro-ET-1 was not different, mRNA for ET-converting enzyme-1 was higher in transgenic sl/sl than in transgenic control lungs. Hypertensive lungs of sl/sl rats also produced less nitric oxide metabolites and 6-ketoprostaglandin F_lα, a metabolite of prostacyclin, than transgenic controls. These findings suggest that the ET_B receptor plays a protective role in the pulmonary hypertensive response to chronic hypoxia.